Phase II Study of Docetaxel in Combination with Everolimus for Second- or Third-Line Therapy of Advanced Non-Small-Cell Lung Cancer

Abstract

We conducted a phase II study of docetaxel in combination with everolimus, a mammalian target of rapamycin (mTOR) inhibitor, for salvage therapy of advanced non–small-cell lung cancer (NSCLC) based on promising preclinical and early-phase clinical data. Patients with advanced-stage NSCLC treated with one or two previous systemic therapy regimens were given docetaxel (60 mg/m²) and everolimus (5 mg orally once daily on days 1–19) every 3 weeks. Archived tumor specimens were evaluated for markers of mTOR pathway activation (total and phosphorylated mTOR, Akt, S6, eIF4e, and 4EBP1). Twenty-eight patients were enrolled (median age: 62 years; male: 13; Caucasians: 19; adenocarcinoma: 20; performance status 0, 3; performance status 1, 23; 1 previous regimen, 16). A median of 3.5 cycles of therapy was administered. Two patients experienced partial response and 15 had stable disease (clinical benefit rate, 70%). The 6-month progression-free survival rate was 5%, and the median overall survival was 9.6 months. Low pAkt expression correlated with clinical benefit rate (p = 0.01) but not with progression-free survival or overall survival. The combination of everolimus and docetaxel was tolerated well, but the efficacy was relatively modest in an unselected population of patients with NSCLC.

The mammalian target of rapamycin (mTOR) regulates cell survival, growth, and metabolism. ¹ It is aberrantly activated in a variety of cancers including non–small-cell lung cancer (NSCLC). Activation of mTOR pathway is also known to contribute to resistance associated with taxane therapy.² Everolimus is an analogue of sirolimus that inhibits the mTOR pathway. The U.S. Food and Drug Administration has approved everolimus for the treatment of advanced renal cell carcinoma. When used as monotherapy in advanced NSCLC, the response rate with everolimus is low at less than 10%.³ In preclinical studies, everolimus exerts synergistic anticancer effects with docetaxel in a variety of cell lines.^4,5 We previously reported that docetaxel and everolimus could be combined safely in patients with advanced NSCLC at the doses of 60 mg/m² and 5 mg orally once daily, respectively.⁶ The dose-limiting toxicities were grade 3 fatigue, grade 3 mucositis, and grade 3/4 neutropenia with fever. Our phase I experience also documented a disease stabilization rate of approximately 55% in patients with advanced NSCLC that had progressed with multiple previous chemotherapy regimens. Therefore, we conducted a phase II study to evaluate the efficacy of the combination of docetaxel and everolimus as salvage therapy in patients with advanced NSCLC.

PATIENTS AND METHODS

Patient Eligibility

Patients with stage IIIB/IV NSCLC that had progressed after one or two previous chemotherapy regimens for advanced NSCLC were eligible. Other salient inclusion criteria were Eastern Cooperative Oncology Group performance status of 0, 1, or 2; life expectancy more than 12 weeks; age more than 18 years; adequate bone marrow, hepatic, and renal function; and willingness to sign informed consent. Women of reproductive age group were required to have a negative serum pregnancy test. Patients with uncontrolled brain metastasis, active bleeding diathesis, use of therapeutic doses of warfarin for anticoagulation, known hypersensitivity to docetaxel, inability to swallow everolimus pills, and/or chronic treatment with systemic corticosteroids or other immunosuppressive agents were excluded. Patients with gastrointestinal dysfunction that could interfere with everolimus absorption, previous therapy with docetaxel, and known seropositivity for human immunodeficiency virus were also excluded. The institutional review board at both the participating institutions approved the study protocol.

Treatment Plan

Docetaxel was administered as a 60-minute intravenous infusion of 60 mg/m² on day 1 of each cycle. Everolimus was prescribed at a dose of 5 mg/day on days 1 to 19 of each cycle. Treatment cycles were repeated every 3 weeks. Prophylactic colony-stimulating factors were not allowed for the first cycle of therapy. Treatment cycles were continued for a maximum of six cycles of therapy, after which patients with stable disease or an objective response were allowed to continue everolimus alone as monotherapy at the same schedule as in the combination regimen. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of informed consent.

Toxicity was graded by the National Cancer Institute Common Terminology Criteria verison 3.0. Dose of the agent most likely to have caused the toxicity was reduced for severe toxicity. Docetaxel was reduced by 10-mg/m² decrements, and everolimus by 2.5-mg/day decrements. A maximum of two dose reductions were allowed per patient, after which he or she had to come off study if further modifications were required. Dose re-escalation was not allowed. Before the initiation of a new cycle of therapy, the patient was required to have an absolute neutrophil count of more than 1500 per cubic microliter and a platelet count of more than 100,000 per cubic microliter. In addition, all treatment-related toxicity had to resolve to grade 1 or less. If these conditions were not met, treatment cycles were delayed up to a maximum of 2 weeks to allow for recovery.

Study Assessments

At baseline, patients were required to undergo a history and physical examination, assessment of performance status, serum pregnancy test (if clinically indicated), complete blood count with differential count, and serum chemistry. Positron emission technique (PET) scan was performed at baseline and after cycle 2. All subsequent assessments were performed with a computed tomography scan every two cycles of therapy. Responses were assessed by the Response Evaluation Criteria in Solid Tumors version 1.0.⁷ For subsequent cycles, history and physical examination, toxicity assessment, complete blood count with differential count, serum chemistry, and lipid profile were evaluated on day 1.

Statistical Methods

The primary objectives of the study were to determine the objective response rate and the 6-month progression-free survival (PFS) rate with the combination of docetaxel and everolimus. The secondary objectives were to evaluate the safety profile and the overall survival. With an estimated sample size of 48 patients, the study would have a 95% power at the 19.7% level of significance to detect an improvement in the 6-month PFS rate from 25% (historical control) to 42% with the novel combination regimen. Twenty-seven patients were enrolled to the first stage of the study. If five or fewer objective responses were observed, the study was to be terminated for lack of efficacy, and more than 12 responses would prompt the termination of the study with acceptance of the alternate hypothesis. PET scans were performed at baseline and after two cycles to determine metabolic response to mTOR inhibition as an exploratory end point.

Biomarker Evaluation

Archival diagnostic tumor samples were evaluated for upstream and downstream markers of mTOR pathway activation (total and phosphorylated mTOR, Akt, S6, eIF4e, and 4EBP1) by immunohistochemistry. The staining intensity of biomarker expression was used for this analysis with the ranges expressed as 0, 1+, 2+, or 3+. General linear models were used to test the differences in biomarker expression across different categories of tumor response and histology. The relationship between the biomarker expression and the patient’s age was assessed by Spearman correlation coefficient and Wald’s test.

RESULTS

Twenty-eight patients were accrued between April 2009 and July 2010. Women and African Americans accounted for 54% and 28% of the study population, respectively. Sixteen patients (58%) had received only one previous chemotherapy regimen (Table 1). The median number of cycles of docetaxel and everolimus combination was 3.5 (range, 1–6). Ten patients received everolimus as maintenance therapy for a median of an additional two cycles (range, 1–7).

TABLE 1.

Patient Demographics

Number of patients	28
Median age	62 years (40–81)
Sex
Male	13
Female	15
Race
Caucasian	19
African American	8
Other	1
Histology
Adenocarcinoma	20
Squamous cell	5
NOS	3
Performance status
0	3
1	23
2	2
Stage
IIIB	2
IV	26
Number of prior regimens
1	16
2	12

NOS, not otherwise specified.

Efficacy

Twenty-four patients completed the first two cycles of therapy and were evaluable per protocol for response determination. Partial responses were observed in two and stable disease in 15, resulting in an overall clinical benefit rate of 71% (Table 2). Of the 28 patients, 20 had documented disease progression during the course of the study, and the median time to disease progression was 4.42 months. The median overall survival was 9.6 months. Paired PET scans were performed in 19 patients. The median standardized uptake value of the dominant tumor mass was 8.3 at baseline (range, 2.8–19) and 7.2 after therapy (range, 3.2–21). There was no correlation between fluorodeoxy glucose uptake and the Response Evaluation Criteria in Solid Tumors responses.

TABLE 2.

Efficacy

Best response (N = 24)	n
Complete response	0 (0)
Partial response	2 (8%)
Stable disease	15 (63%)
Progressive disease	7 (29%)
Median time to progression	4.42 mo
Six-month PFS rate	5%
Median survival	9.6 mo

PFS, progression-free survival.

Toxicity

Neutropenia, anorexia, fatigue, and hyperlipidemia were the most frequently reported toxicities (Table 3). Serious adverse events included fever with neutropenia (n = 3), pneumonia (n = 1), death (n = 1), and small bowel obstruction (n = 1). Six patients were removed from the study because of toxicities. The death resulted from pulmonary embolism as the precipitating event. Among the toxicities, hyperlipidemia, hyperglycemia, and mucositis were likely related to everolimus, whereas the remaining toxicities was attributable to docetaxel alone or the combination regimen.

TABLE 3.

Toxicity^a (represented by worst grade, occurring in at least one patient)

Adverse event (N = 28)	Grade 2	Grade 3	Grade 4
Cough	4	—	—
Leukopenia	2	—	—
Elevated glucose	6	2	—
Low albumin	2	1	—
Back pain	2	—	—
Constipation	2	—	—
Fatigue	9	1	—
Anemia	4	3	—
High cholesterol	2	—	—
Leg pain	2	—	—
Alopecia	1	—	—
Anorexia	3	—	—
Hypertension	1	—	—
Rash	2	—	—
Mucositis	1	1	—
Elevated triglycerides	2	—	—
Lowered phosphorous	2	—	—
Lowered calcium	1	—	—
Pneumothorax	1	—	—
Nail changes	1	—	—
Lowered potassium	1	—	—
Hyperglycemia	1	2	—
Elevated creatinine	1	—	—
Thrombocytopenia	1	—	—
Weight loss	1	—	—
Pain	3	—	—
Peripheral neuropathy	2	—	—
Hypoxia	1	—	—
Infection	2	—	—
Edema	1	—	—
Stomatitis	1	—	—
Dyspnea	1	2	—
Diarrhea	1	—	—
Hyponatremia	—	1	—
Elevated alkaline phosphatase	—	1	—
Small bowel resection	—	1	—
Neutropenia	—	4	—
Dyspepsia	—	1	—
Dizziness	—	1	—
Leucopenia	—	1	—
Hypophosphatemia	—	1	—
Headache	—	1	—
Pneumonia	—	1	—
Thrombosis	—	1	—

^aTreatment discontinuation resulted from severe neutropenia (n = 3), pneumonia (n = 1), decline in performance status (n = 1), and small bowel obstruction (n = 1).

Biomarker Analysis

Tumor samples were available for biomarker analysis in 13 of 28 patients. High pAkt expression was observed in patients with progressive disease (p = 0.01) and in patients with squamous or not otherwise specified histology (p = 0.04). The levels of expression of S6 (p = 0.08), pS6 (p = 0.09), and p-mTOR (p = 0.07) were different among disease-response categories. There was no significant correlation between the tested biomarkers and patient survival outcomes (PFS or overall survival).

DISCUSSION

The promising preclinical and early-phase clinical observations were not confirmed in this phase II study with the combination of docetaxel and everolimus. An important limitation of our study is that the dose of docetaxel at 60 mg/m² is lower than that approved by the U.S. Food and Drug Administration (75 mg/m²). In our preceding phase I study, we were unable to combine the standard dose of docetaxel with a clinically relevant dose of everolimus. The observed median survival of nearly 10 months could have been influenced by poststudy therapy regarding which data were not collected. In studies on lung cancer, everolimus was given at a dose of 5 mg/day, whereas in diseases where it has demonstrated robust efficacy such as breast cancer and renal cancer, it is given at a dose of 10 mg/day.^8,9 This raises the question as to whether at the dose of 5 mg/day, everolimus can exert its effects on upstream and downstream targets in the lung cancer tissue. To assess the differences in the pharmacodynamic effects between the 5mg/day and the 10 mg/day dose, our group is conducting a phase Ib “window of opportunity” study in patients with resectable NSCLC (NCT00401778). The biomarker discovery efforts in our study were limited by the lack of efficacy of the regimen and small number of samples.

Mutations in PIK3CA have been noted in a small proportion of patients with NSCLC and small-cell lung cancer. Evaluation of inhibitors of the PI3K–Akt–mTOR axis in these patients is currently under investigation. If these studies show promising results, then further development of this class of compounds on the basis of pathway activation status in tumor tissues could result in an individualized therapeutic approach for lung cancer.